Hereditary Hemorrhagic Telangiectasia (HHT) is a rare, inherited bleeding disorder caused by mutations in Eng, ALK1 or Smad4. The pathogenesis of HHT involves formation of arteriovenous malformations (AVM) in several tissues and organs including the brain, lung, liver and mucosal membranes. These fragile AVMs are highly prone to bleeding. Of the many clinical manifestations of HHT, recurrent epistaxis and gastrointestinal (small bowel) bleeding are most common; bleeding is chronic, leads to dependence on transfusion and parenteral iron, and significantly impairs quality of life. Treatment for the bleeding manifestations of HHT is supportive, since no effective, non-toxic therapy that causes consistent regression of AVMs has been convincingly demonstrated. The PI's experience with four patients with severe gastrointestinal bleeding from small bowel AVMs, as well as numerous anecdotal reports, suggests that thalidomide causes regression of AVMs and arrests bleeding in patients with HHT. However, thalidomide is not patent protected, is not supplied by the manufacturer for clinical trials and is not produced by manufacturers of generics. Therefore, we propose to design a phase III trial of pomalidomide, a third generation thalidomide analogue with greater anti-angiogenic activity and an improved safety profile, in patients with HHT-related bleeding. We expect to demonstrate feasibility for this trial and activit of pomalidomide for this indication in a 15 patient, industry- funded pilot study in which all patients will be enrolled prior to initiation of this U34. We have assembled a multi-disciplinary, multi-institutional protocol development team that will work with the U24 Clinical Trials Resource to plan the study. Goals of this proposal are 1) To develop a randomized, placebo-controlled phase III study to assess the efficacy and safety of pomalidomide in HHT-related epistaxis and/or gastrointestinal bleeding, and 2) To plan a repository of blood and plasma fractions obtained from patients with HHT before and during pomalidomide therapy that will be used for defining biomarkers of response to pomalidomide and other agents. This proposal utilizes innovative planning strategies to develop a clinical trial of a novel agent that may lead to a new paradigm for treatment of bleeding in patients with HHT.